ZA200404435B - Superoxide dismutase mimics for the treatment of ocular disorders and diseases - Google Patents
Superoxide dismutase mimics for the treatment of ocular disorders and diseases Download PDFInfo
- Publication number
- ZA200404435B ZA200404435B ZA200404435A ZA200404435A ZA200404435B ZA 200404435 B ZA200404435 B ZA 200404435B ZA 200404435 A ZA200404435 A ZA 200404435A ZA 200404435 A ZA200404435 A ZA 200404435A ZA 200404435 B ZA200404435 B ZA 200404435B
- Authority
- ZA
- South Africa
- Prior art keywords
- group
- alkyl
- heteroaryl
- aryl
- alkynyl
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title abstract description 14
- 102000019197 Superoxide Dismutase Human genes 0.000 title description 26
- 108010012715 Superoxide dismutase Proteins 0.000 title description 26
- 208000022873 Ocular disease Diseases 0.000 title description 3
- 201000010183 Papilledema Diseases 0.000 claims abstract description 6
- 206010038886 Retinal oedema Diseases 0.000 claims abstract description 6
- 201000011195 retinal edema Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 12
- -1 akeny Chemical group 0.000 claims description 11
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 206010064930 age-related macular degeneration Diseases 0.000 abstract description 22
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 abstract 1
- 208000002780 macular degeneration Diseases 0.000 description 23
- 206010012601 diabetes mellitus Diseases 0.000 description 15
- 206010012689 Diabetic retinopathy Diseases 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 6
- 210000000608 photoreceptor cell Anatomy 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 5
- 206010030113 Oedema Diseases 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 210000003712 lysosome Anatomy 0.000 description 5
- 239000011572 manganese Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000003642 reactive oxygen metabolite Substances 0.000 description 5
- 210000001525 retina Anatomy 0.000 description 5
- 230000002207 retinal effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000002262 Schiff base Substances 0.000 description 4
- 150000004753 Schiff bases Chemical class 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000001868 lysosomic effect Effects 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 230000000649 photocoagulation Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- 201000004569 Blindness Diseases 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 229940124274 edetate disodium Drugs 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 230000004438 eyesight Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 201000005111 ocular hyperemia Diseases 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical compound O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-HPNHMNAASA-N 11-cis-retinol Natural products OCC=C(C)C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-HPNHMNAASA-N 0.000 description 2
- NCYCYZXNIZJOKI-HPNHMNAASA-N 11Z-retinal Natural products CC(=C/C=O)C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-HPNHMNAASA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 208000001344 Macular Edema Diseases 0.000 description 2
- 206010025415 Macular oedema Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000011717 all-trans-retinol Substances 0.000 description 2
- 229940100609 all-trans-retinol Drugs 0.000 description 2
- 235000019169 all-trans-retinol Nutrition 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 210000003986 cell retinal photoreceptor Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000000254 damaging effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000007323 disproportionation reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000000224 granular leucocyte Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 201000010230 macular retinal edema Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 210000003733 optic disk Anatomy 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 238000005502 peroxidation Methods 0.000 description 2
- CMFNMSMUKZHDEY-UHFFFAOYSA-M peroxynitrite Chemical compound [O-]ON=O CMFNMSMUKZHDEY-UHFFFAOYSA-M 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 101150017120 sod gene Proteins 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006055 1-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KGWNHXCBHOVEOM-UHFFFAOYSA-N 2-pyridin-1-ium-1-ylethanol Chemical compound OCC[N+]1=CC=CC=C1 KGWNHXCBHOVEOM-UHFFFAOYSA-N 0.000 description 1
- 102000043966 ABC-type transporter activity proteins Human genes 0.000 description 1
- 108010006533 ATP-Binding Cassette Transporters Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- YUWPMEXLKGOSBF-GACAOOTBSA-N Anecortave acetate Chemical compound O=C1CC[C@]2(C)C3=CC[C@]4(C)[C@](C(=O)COC(=O)C)(O)CC[C@H]4[C@@H]3CCC2=C1 YUWPMEXLKGOSBF-GACAOOTBSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 241000689227 Cora <basidiomycete fungus> Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022680 Intestinal ischaemia Diseases 0.000 description 1
- 102000014944 Lysosome-Associated Membrane Glycoproteins Human genes 0.000 description 1
- 108010064171 Lysosome-Associated Membrane Glycoproteins Proteins 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 206010057430 Retinal injury Diseases 0.000 description 1
- 244000292604 Salvia columbariae Species 0.000 description 1
- 235000012377 Salvia columbariae var. columbariae Nutrition 0.000 description 1
- 235000001498 Salvia hispanica Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000027073 Stargardt disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- ANXJVMZTCUUZPS-UHFFFAOYSA-N [Mn].OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Mn].OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 ANXJVMZTCUUZPS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 125000000033 alkoxyamino group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960001232 anecortave Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940082649 blood substitutes and perfusion irrigating solutions Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 210000001775 bruch membrane Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000014167 chia Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 230000001904 diabetogenic effect Effects 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002497 edematous effect Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000013628 high molecular weight specie Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical group CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical group C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000013010 irrigating solution Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000004707 phenolate Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 150000003726 retinal derivatives Chemical class 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 210000003994 retinal ganglion cell Anatomy 0.000 description 1
- 230000004232 retinal microvasculature Effects 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 108010045815 superoxide dismutase 2 Proteins 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- YTZALCGQUPRCGW-ZSFNYQMMSA-N verteporfin Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(CCC(=O)OC)=C(C)C(N3)=C3)=N2)C)=C(C=C)C(C)=C1C=C1C2=CC=C(C(=O)OC)[C@@H](C(=O)OC)[C@@]2(C)C3=N1 YTZALCGQUPRCGW-ZSFNYQMMSA-N 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 229940061392 visudyne Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The use of SOD mimics particularly pentaazacycle Mn(II) complex SOD mimics, for the treatment of AMD, DR, and retinal edema is disclosed.
Description
SUPEROXIDE DISMUTASE MIMICS FOR THE TREATMENT OF OCULAR
DISORDERS AND DISEASES s The present invention relates to mimics of the enzyme superoxide dismutase for the treatment of the exudative and non-exudative forms of age- related macular degeneration, diabetic retinopathy, and retinal edema.
Age-related macular degeneration (AMD) is the most common cause of vision impairment in the elderly population in western countries. The exudative or “wet” form of AMD is characterized by excessive neovascularization of the choroid, leading to retinal detachment and vision
Is loss. The non-exudative or “dry” form is characterized by the accumulation of cellular debris called drusen in Bruch's membrane below the retinal pigmented epithelium (RPE). Exudative AMD, which occurs in a minority of patients with AMD, but is the more aggressive form of the disease, can be treated with limited success by laser photocoagulation therapy or photodynamic therapy. The latter procedure involves dosing of the affected area with a compound which, when irradiated with the appropriate wavelength of light, generates a reactive intermediate that destroys surrounding blood vessels. Currently there is no accepted therapy for the treatment of non- exudative AMD.
The visual cycle begins in photoreceptor cells with the absorption of a photon by an opsin-bound Schiff base of 11-cis retinal, which isomerizes to the corresponding all-trans retinal derivative. Release of the all-trans retinal from opsin is followed by condensation with phosphatidylethanolamine to form the new Schiff base NRPE (for N-Retinyl Phosphatidyl Ethanolamine).
The NRPE so formed is transported across the photoreceptor cell outer membrane, where it is hydrolyzed to all-trans retinal. Enzymatic reduction to all-trans retinol is followed by transport into the RPE cell, where the compound is enzymatically isomerized to 11-cis retinol and oxidized to 11-cis 3s retinal. This compound is transported back to the photoreceptor cell, where it forms an opsin-bound Schiff base to complete the cycle.
XX N v 3 hvdrolysis SORE + HN dem =n on) all-trans retinal ttisatiri rien ? - OR
ROY o-p-om S CORA a phosphatidylethanolamine NRPE © all-trans retinol z Zz 11-cis retinol OH 11-cis retinal
Besides helping to complete the visual cycle by recycling retinal, an important function of RPE cells is to support the continuous remodeling of retinal photoreceptors by phagocytosing their discarded outer segments and digesting them in RPE cell lysosomes. With age occurs the accumulation of a non-digestible pigment called lipofuscin in the lysosomes (the appearance of drusen is thought to correspond to lipofuscin accumulation). Lipofuscin absorbs light in the blue part of the spectrum and fluoresces in the yellow part of the spectrum. This fluorescence transfers energy to nearby oxygen, which becomes transformed into reactive oxygen species (ROS), such as superoxide ion. These ROS oxidize lysosomal membrane phospholipids, destroying membrane integrity. With membrane integrity breached the toxic 1s contents of the lysosome leach into the cytosol, leading to RPE cell death.
Without their supporting RPE cells retinal photoreceptors cannot participate in the visual transduction system, thus leading to blindness (for a review, see
Winkler, et. al, Mol. Vision, Vol. 5:32, 1999, online journal, http://www.molvis.org/molvisiv5/p32; CA 132:235390).
Nakanishi and co-workers have elucidated the structure of and chemically synthesized the major fluorescent constituent of lipofuscin, called
A2E (Nakanishi et. al., Proc. Natl. Acad. Sci. USA, Vol. 95:14609-14613, 1998, and references therein). This compound is thought to result biosynthetically from isomerization of electrophilic NRPE to the nucleophilic enamine 1, followed by condensation with another molecule of all-trans retinal to form azatriene 2, electrocyclic ring closure to dihydropyridine 3, autoxidation to the N-(2-hydroxyethyl)pyridinium species A2PE, and enzyamtic hydrolysis of the phosphate ester by the enzyme phospholipase D to afford A2E. The chemical structure of A2E-a molecule with two large hydrophobic “tails” and a charged polar “head-suggests a detergent-like propensity to breach cell membranes. Along with its photooxidative capabilities, this may form an important component of the compound's toxic effects on RPE cells (for a review, see: Nakanishi et. al, Bioorganic and
Medicinal Chemistry Letters, Vol. 11:1533-1540, 2001).
HN—\_-0Z
CS Ae CAA
NRPE o- OR 1 ,- pO OR lo] = RS = A x IAN =X AN "~~ 0Z Ni 0Z
NaN = NA
SQatas
IAN N
AN = x AN xX N
ZN. 0Z Z NOH
NAN ! Na SN !
A2PE A2E
The key role of defective transport of all-trans retinal out of the photoreceptor cell in the AMD disease process has been highlighted by the discovery that a genetic mutation that when homozygously present leads to a rare rapid macular degeneration called Stargardt's Disease may be s associated, when heterozygously expressed, with non-exudative AMD (Dean et. al, Science, Vol. 277:1805-1807, 1997). The gene is called the ABCR gene (for ATP Binding Cassette Transporter Retina), whose protein product (also called rim protein) utilizes the energy released upon ATP hydrolysis to transport molecules across cell membranes. It is thought that the transporter's substrate is the Schiff base NRPE mentioned above. Absent sufficient functional transporter protein, the substrate NRPE accumulates in the photoreceptor cell instead of being shuttled out for reduction to retinol.
Condensation with a molecule of all trans-retinal liberated from opsin and further reaction as mentioned above produces A2E. The A2E is ingested by 1s RPE cells with the rest of the photoreceptor cell outer segment, where it accumulates in the lysosome. Supporting this hypothesis is the disclosure by
Travis et. al. that A2E accumulation in RPE cells occurs much more rapidly in mice that are homozygously mutant in the ABCR gene, as compared to normal controls (Travis et. al., Proc. Natl. Acad. Sci. USA, Vol. 97:7154-71589, 2000).
Several studies have concluded that exposure of lipofuscin to light and oxygen under conditions mimicking those present in the retina leads to cell membrane peroxidation and cell death. Wihimark et. al. disclosed that blue light irradiation of RPE cells with lipofuscin-loaded lysosomes increased cell membrane peroxidation and decreased cell viability, as compared to controls irradiated in the absence of lipofuscin (Wihimark et. al, Free Radical Biol.
Med. Vol. 22:1229-1234, 1997). Boulton and Shamsi have disclosed that dosing of cultured RPE cells with lipofuscin and exposing them to light decreased cell viability by over 40% after 24 hours and decreased lysosomal enzymatic and antioxidant activity, including that of superoxide dismutase (SOD) (Boulton and Shamsi, Invest. Ophthalmol. Vis. Sci., Vol. 42:3041-3046, 2001).
From this and other evidence, it is clear that certain defects in the body's natural defense mechanisms for dealing with toxic by-products of oxidative metabolism may play an important role in the development of AMD.
One important component of this defense system is the SOD enzyme family.
These enzymes contain a low valent metal (either Mn" or a Cu'/zn' binuclear linkage) which catalyze the disproportionation of the highly reactive superoxide radical anion to the less toxic entities O; and H,0,. If not quenched the superoxide anion can (via its protonated form) abstract s hydrogens from the allylic sites of fatty acids, leading to membrane damage.
Additionally superoxide anion can react with NO to produce peroxynitrite, a potent oxidizing agent that is believed to be an important player in the untoward biological effects of excessive NO production. _ SoD . _ 2H*+2°0, —— H,0,+0, "0, * NO — 0ONOO peroxynitrite
The potential importance of SOD in enhancing RPE cell viability is suggested by the disclosure of Boulton et. al, who. have reported that the damaging effects caused by irradiation of lipid membranes, proteins, and enzymes in the presence of lipofuscin can be significantly reduced by the addition of SOD (Boulton et. al., J Biol. Chem., Vol. 274:23828-23832, 1999).
Even with respect to exudative AMD, a recent study in Japanese subjects disclosed a significant correlation between this form of the disease and a mutation in the SOD gene, corresponding to a valine/alanine substitution in the targeting sequence of the enzyme (Isashiki et. al., Am. J. Ophthalmol,
Vol. 130:769-773, 2000). Thus, enhancing SOD function may be a viable target for preventing the development of both the exudative and non- exudative forms of AMD.
Oxidative stress also contributes to diabetes induced vascular and neural dysfunction. All forms of diabetes result in the development of diabetes specific microvascular pathology of the retina, renal glomerulus and peripheral nerve (M. Brownlee, ‘Biochemistry and Molecular Cell Biology of
Diabetic Complications”, Nature, Vol. 414:813-820, 2001). A prime source of the oxidative insult associated with diabetes is elevated levels of superoxide.
Release of superoxide was detected in human blood vessels isolated from, patients with diabetes (Guzik, et al. “Mechanisms of Increased Vascular
Superoxide Production in Human Diabetes Mellitus” Circulation,
Vol. 105:1656-62, 2002). Sources of superoxide include the vascular tissues 38 and polymorphonuclear leukocytes (Shurtz-Swirski et al, “Involvement of
Peripheral Polymorphonuclear Leukocytes in Oxidative Stress and
Inflammation in Type 2 Diabetic Patients,” Diabetes Care, Vol. 24:104-110,
2001). Superoxide Dismutase mimics have been shown to delay the onset of diabetes (AEOL10113 — Piganelli, et al, "A Metalloporphyrin-Based
Superoxide Dismutase Mimic Inhibits Adoptive Transfer of Autoimmune
Diabetes by a Diabetogenic T-cell Clone,” Diabetes, Vol. 51:347-55, 2002.) in a cloned cell and prevented vascular and neural dysfunction in diabetic rats (M40403 — Coppey, et al., “Effect of M40403 Treatment of Diabetic Rats on
Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular
Function of Epineural Arterioles of the Siatic Nerve,” British Journal of
Pharmacology, Vol. 134:21-9, 2001). In patients with diabetic retinopathy serum level of lipid peroxides are higher than in healthy normals or patients with diabetes that do not have diabetic retinopathy. While levels of SOD remain the same in diabetics and normals, levels of ascorbic acid, a key anitoxidant, are lower in all diabetics (Gurler, et al., “The Role of Oxidative
Stress in Diabetic Retinopathy’ Eye, Vol. 14:73035, 2000) The results of these studies suggest that endogenous antioxidant mechanisms are overwhelmed in patients with diabetic retinopathy.
The use of intravenously dosed Mn SOD itself to treat or prevent oxidative stress-related tissue injury in humans, such as tissue damage due to cerebral or myocardial ischemia-reperfusion injury, has been unsuccessful due to bioavailability and immunogenic issues. These problems are thought to be due to the fact that Mn SOD is a high molecular weight species. A low molecular weight compound that catalyzes superoxide disproportionation with efficiency comparable to endogenous Mn SOD would be a good candidate for minimizing the aforementioned side effects. Salvemini et. al. have disclosed a class of Mn(ll)-pentaaza macrocycle complexes as low molecular weight
SOD mimics. For example, in a rat model of intestinal ischemia-reperfusion, 90% of animals dosed with 1 mg/kg of compound 4 survived after 4 h, compared to 0% survival for untreated animals [Salvemini, et. al., Science,
Vol. 286:304, 1999; WO 98/58636; Saivemini, et al, Drugs Future, Vol. 25(10):1027, 2000}, These compounds have also been disclosed for enhancing the stability of implanted biopolymeric prosthetic devices (including ocular implants; Ornberg et. al., WO 00/72893 A2) and for the treatment of pain (Salvemini et. al., U.S. Patent Nos. 6,180,620 B1 and 6,214,817B1).
lS
CHO
HY
4
The use of certain Mn-salen complexes as SOD and catalase mimics with therapeutic activity has also been disclosed. For example, compound § has been shown to be neuroprotective in a rat stroke model (Baker et. al., J. s Pharmacol. Exp. Ther., Vol. 284:215-221, 1998; Doctrow et. al, J. Med.
Chem., Vol. 45:4549-4558, 2002), while compound 6 was found to increase the lifespan of mice that were deficient in endogenous expression of the enzyme superoxide dismutase 2 (Melov et. al., J. Neurosci., Vol. 21:8348- 8353, 2001). 10 yl Hl
Mn Mn
CB CHE of OAc
OMe MeO OEt EtO 6
Other investigators have reported the use of antioxidant compounds to treat ocular diseases. Crapo et. al., have disclosed the use of porphyrin- is containing SOD mimics for treating glaucoma and macular degeneration (Crapo et. al, U.S. Patent Nos. 5,994,339 and 6,127,356). Campbell et. al. have disclosed the use of certain bipyridyl Mn(ll or Ill)phenolate complexes for treating free-radical associated diseases (Campbell et. al., U.S. Patent No. 6,177,419 B1). Levin has disclosed the use of carvedilol and its derivatives and metabolites as scavengers of ROS to reduce retinal ganglion cell death (WO 00/07584 A2). Brownlee has disclosed the use of a manganese tetrakis(benzoic acid) porphyrin for reducing ROS accumulation under high glucose conditions for treating diabetic retinopathy (Brownlee, WO 00/19993
A2). The stable free radical 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, a 2s metal-free SOD mimic, has been reported to inhibited light-induced retinal damage in albino rats (Wang et. al., Res. Commun. Mol. Pathol. Pharmacol.
Vol. 89:291-305, 1995). However, in none of these reports were the compounds of the present invention disclosed or suggested for the treatment of AMD.
This application is directed to the use of mimics of the enzyme, superoxide dismutase to treat persons suffering from the exudative and non- exudative forms of AMD, diabetic retinopathy, which includes preproliferative diabetic retinopathy (collectively DR) and retinal edema.
Posterior segment neovascularization is the vision-threatening pathology responsible for the two most common causes of acquired blindness in developed countries: exudative age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). Currently the only approved 1s treatments for the posterior segment NV that occurs during exudative AMD are laser photocoagulation or photodynamic therapy with Visudyne®; both therapies involve occlusion of affected vasculature which results in localized laser-induced damage to the retina. Surgical interventions with vitrectomy and membrane removal are the only options currently available for patients with proliferative diabetic retinopathy. No strictly pharmacologic treatment has been approved for use against posterior segment NV, although several different compounds are being evaluated clinically, including, for example, anecortave acetate (Alcon, Inc.), EYE 001 (Eyetech), and rhuFabV2 (Genentech) for AMD and LY333531 (Lilly) and Fluocinolone (Bausch &
Lomb) for diabetic macular edema.
In addition to changes in the retinal microvasculature induced by hyperglycemia in diabetic patients leading to macular edema, proliferation of neovascular membranes is also associated with vascular leakage and edema of the retina. Where edema involves the macula, visual acuity worsens. In diabetic retinopathy, macular edema is the major cause of vision loss. Like angiogenic disorders, laser photocoagulation is used to stabilize or resolve the edematous condition. While reducing further development of edema, laser photocoagulation is a cytodestructive procedure, that, unfortunately will alter the visual field of the affected eye.
An effective pharmacologic therapy for ocular NV and edema would likely provide substantial efficacy to the patient, in many diseases thereby avoiding invasive surgical or damaging laser procedures. Effective treatment of the NV and edema would improve the patient's quality of life and productivity within society. Also, societal costs associated with providing assistance and health care to the blind could be dramatically reduced. s It has now been discovered that certain SOD mimics are useful for the treatment of AMD, DR, and retinal edema. These compounds are of formula poet LT TR
Ry; Ris Ts
Ris H ) X H
Rye N I N- Ry
I ang
LAVACA
R11 h 1) Rs
ReRio Ry Ry
I wherein:
R"# are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is optionally substituted with an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalky!, heterocycloalkenyl, halo, trihalomethyl, acyl,
Is alkoxycarbonyl, alkylsulfony), or arylisulfonyl group, or a free or functionally modified hydroxyl, amino, or thiol group; or two of the R groups on the same (e.g., Rand R? or R® and R* or R® and
R®, etc.) or adjacent (e.g, R* and R>, or R® and R®, or R® and R’, etc) sites, together with the carbon atoms to which they are attached, form an optionally unsaturated or aromatic Ci.y carbocycle, the carbocycle being optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or arylsulfonyl group, or a free or functionally 28 modified hydroxyl, amino, or thiol group; or two of the R groups on the same (e.g, R' and R?, or R® and R* or R® and
R®, efc.) or adjacent (e.g, R' and R or R® and R®, or R® and R’, etc) sites, together with the carbon atoms to which they are attached, form an optionally unsaturated or aromatic C.,.5 nitrogen-containing heterocycle, the heterocycle being optionally substituted optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl,
halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or arylsuifonyl group, or a free or functionally modified hydroxyl, amino, or thiol group; it being understood that in all cases the nitrogens binding the Mn center in the drawing for | will lack hydrogens when the nitrogen is already trisubstituted (e.g., when the relevant nitrogen is part of a pyridine ring);
X,Y, and Z are pharmaceutically acceptable anions; and nis 0-3.
Compounds 1 of the present invention are known, and their syntheses are disclosed in US Patent No. 6,214,817 B1, which is herein incorporated by reference.
As used herein, the terms “pharmaceutically acceptable anion” means any anion that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences.
Examples of preferred pharmaceutically acceptable anions include chloride, bromide, acetate, benzoate, maleate, fumarate, and succinate.
The term “free hydroxy group” means an OH. The term “functionally modified hydroxy group” means an OH which has been functionalized to form: an ether, in which an alkyl group is substituted for the hydrogen; an ester, in which an acyl group is substituted for the hydrogen; a carbamate, in which an aminocarbonyl group is substituted for the hydrogen; or a carbonate, in which an alkoxycarbonyl group is substituted for the hydrogen. Examples of preferred groups include OH,0C(O)CH;3, OCH; OPh, OCH:Ph, and
OC(O)Ph.
The term “free amino group” means an N,. The term “functionally modified amino group” means an NHz which has been functionalized to form: an alkoxyamino or hydroxyamino group, in which an alkoxy or hydroxy group is substituted for one of the hydrogens; an alkylamino group, in which an alkyl group is substituted for one or both of the hydrogens; an amide, in which an acyl group is substituted for one of the hydrogens; a carbamate, in which an alkoxycarbonyl group is substituted for one of the hydrogens; or a urea, in which an aminocarbonyl group is substituted for one of the hydrogens.
Combinations of these substitution patterns, for example an NH; in which one of the hydrogens is replaced by an alkyl group and the other hydrogen is replaced by an alkoxycarbonyl group, also fall under the definition of a ’ functionally modified amino group and are included within the scope of the [4 present invention. Examples of preferred groups include NH,, NHCHs3,
N(CHa)2, NHPh, NHC(O)Ph, NHC(O)CHj3, NHC(O)OCH;,, and NHC(O)OPh.
The term “free thiol group” means an SH. The term “functionally modified thiol group” means an SH which has been functionalized to form: a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; or a thioester, in which an acyl group is substituted for the hydrogen. Examples of preferred moieties include SH, SPh, SC(O)CHs,
SCHs, SC2Hs, SC(CHa3)s, S-cyclohexyl, SCH,CO,CH;, SCH,CO,C,H;,
SCH;C(O)C,Hs, and SCH,C(O)CHia.
The term “acyl” represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to another carbon atom.
The term “alkyl” includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and -butyl.
The term “cycloalkyl” includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “alkenyl” includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double 3s bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkeny groups include, allyl, 1- butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term “cycloalkenyl” includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings containing a carbon-carbon double bond, which can he fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
The term “alkoxy” represents an alkyl group attached through an oxygen linkage.
The term “carbonyl group” represents a carbon atom double bonded to an oxygen atom, wherein the carbon atom has two free valencies.
The term “alkoxycarbonyl” represents an alkoxy group bonded from its 1s oxygen atom to the carbon of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.
The term “aminocarbonyl” represents an amino group bonded from its nitrogen atom to the carbon atom of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.
The term “lower alkyl” represents alkyl groups containing one to six carbons (C,-Cyg).
The term “halogen” represents fluoro, chloro, bromo, or iodo.
The term “aryl” refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
The term “heteroaryl” refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.
The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan,
thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
Preferred compounds of the present invention include those of formula
H I, wherein:
R’R’C-N-CR°R" forms a 5-8 membered saturated or unsaturated (including aromatic) ring, the ring being optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or arylsulfonyl group, or a free or functionally modified hydroxyl, amino, or thiol group;
R%, R® R", R™, R", R"™ R'™, and R® are the same or different and are H or alkyl;
R'R?C-CR®R* and RR™C-CR"R'® are the same or different and form a 5-8 membered saturated or unsaturated (including aromatic) ring, the ring being optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or arylsulfonyl group, or a free or functionally modified hydroxyl, amino, or thiol group;
X and Y are chloride; and nis 0.
The most preferred compounds of the present invention include the following:
JOR WON . | g
ER lS if
FO CHRO CERO
= HSH SHI < HIN 4 5 6 sO A -N.o
N N LL
H) 1S NH H.) [CH HY CH
N NEN be N MA I. N MAN re
CA a) CoO CoO 7 8 9
The syntheses of these compounds is disclosed in U.S. Patent
No. 6,214,817 B1.
The SOD mimics may be contained in various types of pharmaceutical compositions, in accordance with formulation techniques known to those skilled in the art. For example, the compounds may be included in tablets, capsules, solutions, suspensions, and other dosage forms adapted for oral administration: solutions and suspensions adapted for parenteral use; and solutions and suspensions adapted for topical ophthalmic, depot, or intra- ocular injection. Solutions, suspensions, and other dosage forms adapted for depot, oral, intra-ocular injection, and topical ophthalmic administration, such as eye drops or tissue irrigating solutions, are particularly preferred for the prevention or treatment of acute or chronic retinal or optic nerve head damage. Compositions can also be delivered topically to the eye according to the teachings in WO 96/05840, which is herein incorporated by reference.
The present invention is also directed to the provision of compositions adapted for treatment of retinal and optic nerve head tissues. The ophthalmic compositions of the present invention will include one or more SOD mimics and a pharmaceutically acceptable vehicle. Various types of vehicles may be used. The vehicles will generally be aqueous in nature. Aqueous solutions are generally preferred, based on ease of formulation, as well as a patient's ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the SOD mimics of the present s invention may also be readily incorporated into other types of compositions, such as suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for SOD mimics that are relatively insoluble in water. The ophthalmic compositions of the present invention may also include various other ingredients, such as buffers, preservatives, co-solvents, and viscosity building agents.
An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium borate) may be added to prevent pH drift under storage conditions.
Ophthalmic products are typically packaged in multidose form.
Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% weight/volume (*% wiv").
The route of administration (e.g., topical, ocular injection, parenteral, or oral) and the dosage regimen will be determined by skilled clinicians, based on factors such as the exact nature of the condition being treated, the severity of the condition, and the age and general physical condition of the patient.
In general, the doses used for the above described purposes will vary, but will be in an effective amount to prevent or treat AMD, DR, and retinal edema. As used herein, the term ‘pharmaceutically effective amount” refers to an amount of one or more SOD mimics which will effectively treat AMD,
DR, and/or retinal edema in a human patient. The doses used for any of the above-described purposes will generally be from about 0.01 to about 100 milligrams per kilogram of body weight (mg/kg), administered one to four times per day. When the compositions are dosed topically, they will generally be in a concentration range of from 0.001 to about 5% w/v, with 1-2 drops administered 1-4 times per day.
As used herein, the term “pharmaceutically acceptable carrier” refers to any formulation that is safe, and provides the appropriate delivery for the desired route of administration of an effective amount of at least one compound of the present invention.
The following Examples 1 and 2 are formulations useful for intraocular, periocular, or retrobulbar injection or perfusion.
EXAMPLE 1
Component % wiv
Compound of formula | 0.1
Dibasic sodium phosphate 0.2
HPMC 0.5
Polysorbate 80 0.05
Benzalkonium chloride 0.01
Sodium chloride 0.75
Edetate disodium 0.01
NaOH/HCI gs.topH74
Purified water q.s. to 100%
EXAMPLE 2
Component % wiv
Compound of formula | 0.1
Cremophor EL 10
Tromethamine 0.12
Boric acid 0.3
Mannitol 4.6
Edetate disodium 0.1
Benzalkonium chloride 0.1
NaOH/HCI gs.topH74
Purified water g.s. to 100%
EXAMPLE 3 s
The following tablet formulation can be made pursuant to U.S. Patent
No. 5,049,586, incorporated herein by reference.
Component % wiv
Compound of formula | 60
Magnesium oxide 20
Corn starch 15
Polyvinylpyrrolidone 3
Sodium 1 carboxymethylcellulose
Magnesium stearate 0.8
The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.
Claims (4)
1. Use of a compound of formula R, Rig (a Ris H ) X H Ris N | R4 Rg a Yani Ris" H Y \ Ry Roe | “on, N " NH Re Rs RaRiwo R, Ry ! wherein: R"¥ are independently H, alkyl, akeny, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyi, or heterocycloalkenyl, each of which is optionally substituted with an alkyl, akenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or arylsulfonyl group, or a free or functionally modified hydroxyl, amino, or thiol group; or two of the R groups on the same (e.g., R' and R?, or R® and R*. or RS and R®, etc.) or adjacent (e.g., R' and R®. or R® and R®, or R® and R, etc.) sites, together with the carbon atoms to which they are attached, form an optionally unsaturated or aromatic Csz carbocycle, the carbocycle being optionally substituted with alkyl, alkenyl, alkynyl, cycloakyl, Cycloakenyl, aryl, heteroaryl, heterocycloalkyl, heterocycioalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or arylsuifonyl group, or a fres or functionally modified hydroxyl, amino, or thiol group; or two of the R groups on the same (e.g., R' and R?, or R? and R* or R® and R®, ofc.) or adjacent (e.g., R' and R®, or R® and R® or R® and R’, ofc.) sites, together with the carbon atoms to which they are attached, form an optionally unsaturated or aromatic C,.» nitrogen-containing heterocycle, the heterocycle being optionally substituted optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloaikenyl, -19- AMENDED SHEET halo, trihalomethyl, acyl, alkoxycarbonyl, akytsulfonyl, or aryisulfonyl group, or a free or functionally modified hydroxyl, amino, or thiol group; it being understood that in all cases the nitrogens binding the Mn center in the drawing for | will lack hydrogens when the nitrogen is already trisubstituted
(e.g., when the relevant nitrogen is part of a pyridine ring); X,Y, and Z are pharmaceutically acceptable anions; and nis 0.3, in the manufacture of a medicament for treating AMD, DR, and/or retinal edema in a patient.
2. The use of claim 1, wherein for the compound of formula I: R'R°C-N-CRR' forms a 5-8 membered saturated of unsaturated (including aromatic) ring, the ring being optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloakenyt, aryl, heteroaryl, heterocycloalkyi, heterocycloalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, alkylsulfonyl, or aryisulfonyi group, or a free or functionally modified hydroxyl, amino, or thiol group; R% R% R", R?, RY, R"®, R™ and R? are the same or different and are H or alkyt; R'R’C-CR’R* and RPR"“C-CR™R" are the same of different and form a 5-8 membered saturated or unsaturated (including aromatic) ring, the ring being optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteracycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl, alkoxycarbonyl, akylisulfonyl, or aryisulfonyl group, or a free or functionally modified hydroxyl, amino, or thiol group; X and Y are chloride; and nis 0. -20- AMENDED SHEET
3. The use of claim 1, wherein the compound is selected from the group NZ N° N° THRO EO * Forty d rh vii ry oi) or 3 N Oly Gly and aly pe nn uN CeO TBO CSO o H H H + H H consisting of.
4, The use of claim 1 substantially as herein described and exemplified. 21- AMENDED SHEET :
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US34038901P | 2001-12-14 | 2001-12-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200404435B true ZA200404435B (en) | 2006-05-31 |
Family
ID=23333158
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200404435A ZA200404435B (en) | 2001-12-14 | 2004-06-04 | Superoxide dismutase mimics for the treatment of ocular disorders and diseases |
Country Status (19)
Country | Link |
---|---|
US (2) | US7759333B2 (en) |
EP (1) | EP1463563B1 (en) |
JP (1) | JP2005513063A (en) |
KR (1) | KR100951606B1 (en) |
CN (2) | CN1620325A (en) |
AT (1) | ATE422944T1 (en) |
BR (1) | BR0214957A (en) |
CA (1) | CA2470721C (en) |
CY (1) | CY1108983T1 (en) |
DE (1) | DE60231246D1 (en) |
DK (1) | DK1463563T3 (en) |
ES (1) | ES2319399T3 (en) |
HK (1) | HK1069785A1 (en) |
MX (1) | MXPA04005601A (en) |
PL (1) | PL210225B1 (en) |
PT (1) | PT1463563E (en) |
SI (1) | SI1463563T1 (en) |
WO (1) | WO2003051458A1 (en) |
ZA (1) | ZA200404435B (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1463563T3 (en) * | 2001-12-14 | 2009-04-20 | Alcon Inc | Super oxide dismutas mimetics for the treatment of eye disorders and diseases |
JP2007513948A (en) * | 2003-12-11 | 2007-05-31 | アルコン,インコーポレイテッド | Superoxide dismutase mimics for the treatment of optic nerve damage and retinal damage |
US7803931B2 (en) | 2004-02-12 | 2010-09-28 | Archemix Corp. | Aptamer therapeutics useful in the treatment of complement-related disorders |
US8987245B2 (en) | 2008-04-02 | 2015-03-24 | Jonathan R. Brestoff Parker | Composition and method for affecting obesity and related conditions |
US8598150B1 (en) | 2008-04-02 | 2013-12-03 | Jonathan R. Brestoff | Composition and method for affecting obesity and related conditions |
CR20110389A (en) | 2008-12-19 | 2011-07-13 | Abbott Lab | COMPOUNDS AND METHODS OF USE |
EP2433640B1 (en) | 2010-09-24 | 2020-01-15 | OmniVision GmbH | Composition comprising SOD, lutein and zeaxanthin |
KR101214364B1 (en) * | 2011-02-15 | 2012-12-21 | 한림대학교 산학협력단 | Pharmaceutical composition for eye disease containing superoxide dismutase fusion protein |
US9149483B2 (en) * | 2011-09-26 | 2015-10-06 | Galera Labs, Llc | Methods for treatment of diseases |
KR102531246B1 (en) * | 2021-12-23 | 2023-05-11 | 주식회사 제노포커스 | Superoxide dismutase and uses thereof for preventing or treating dry macular degeneration |
WO2023224136A1 (en) * | 2022-05-16 | 2023-11-23 | 주식회사 제노포커스 | Superoxide dismutase and uses thereof for preventing or treating diabetic retinopathy or uveitis |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5209926A (en) | 1990-06-12 | 1993-05-11 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
US5124154A (en) * | 1990-06-12 | 1992-06-23 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
US5994339A (en) | 1993-10-15 | 1999-11-30 | University Of Alabama At Birmingham Research Foundation | Oxidant scavengers |
US6127356A (en) | 1993-10-15 | 2000-10-03 | Duke University | Oxidant scavengers |
SE9402816D0 (en) | 1994-08-24 | 1994-08-24 | Pharmacia Ab | Method and meams for drug administration |
US6214817B1 (en) * | 1997-06-20 | 2001-04-10 | Monsanto Company | Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity |
US6180620B1 (en) | 1997-06-20 | 2001-01-30 | G.D. Searle & Co. | Analgesic methods using synthetic catalysts for the dismutation of superoxide radicals |
JP2001521939A (en) * | 1997-11-03 | 2001-11-13 | デューク・ユニバーシティー | Substituted porphyrins |
US6291506B1 (en) | 1998-08-04 | 2001-09-18 | Wisconsin Alumni Research Foundation | Method of reducing retinal ganglion cell degeneration |
GB9817845D0 (en) | 1998-08-17 | 1998-10-14 | Glaxo Group Ltd | Chemical compounds |
WO2000023568A2 (en) | 1998-10-06 | 2000-04-27 | Albert Einstein College Of Medicine Of Yeshiva University | Methods and compositions for decreasing mitochondrial overproduction of reactive oxygen species in cells |
ATE291446T1 (en) | 1999-05-27 | 2005-04-15 | Monsanto Co | BIOMATERIALS MODIFIED WITH SUPEROXIDE DISMUTASE MIMITATORS |
DK1463563T3 (en) * | 2001-12-14 | 2009-04-20 | Alcon Inc | Super oxide dismutas mimetics for the treatment of eye disorders and diseases |
-
2002
- 2002-12-06 DK DK02786915T patent/DK1463563T3/en active
- 2002-12-06 CN CNA028280806A patent/CN1620325A/en active Pending
- 2002-12-06 BR BR0214957-5A patent/BR0214957A/en not_active Application Discontinuation
- 2002-12-06 PT PT02786915T patent/PT1463563E/en unknown
- 2002-12-06 ES ES02786915T patent/ES2319399T3/en not_active Expired - Lifetime
- 2002-12-06 DE DE60231246T patent/DE60231246D1/en not_active Expired - Lifetime
- 2002-12-06 JP JP2003552386A patent/JP2005513063A/en active Pending
- 2002-12-06 KR KR1020047008842A patent/KR100951606B1/en not_active IP Right Cessation
- 2002-12-06 CA CA2470721A patent/CA2470721C/en not_active Expired - Fee Related
- 2002-12-06 SI SI200230808T patent/SI1463563T1/en unknown
- 2002-12-06 EP EP02786915A patent/EP1463563B1/en not_active Expired - Lifetime
- 2002-12-06 AT AT02786915T patent/ATE422944T1/en active
- 2002-12-06 PL PL369607A patent/PL210225B1/en unknown
- 2002-12-06 MX MXPA04005601A patent/MXPA04005601A/en active IP Right Grant
- 2002-12-06 US US10/498,721 patent/US7759333B2/en not_active Expired - Fee Related
- 2002-12-06 CN CNA2006100774968A patent/CN101092432A/en active Pending
- 2002-12-06 WO PCT/US2002/039037 patent/WO2003051458A1/en active IP Right Grant
-
2004
- 2004-06-04 ZA ZA200404435A patent/ZA200404435B/en unknown
-
2005
- 2005-03-17 HK HK05102326.6A patent/HK1069785A1/en not_active IP Right Cessation
-
2009
- 2009-04-14 CY CY20091100442T patent/CY1108983T1/en unknown
-
2010
- 2010-04-23 US US12/766,332 patent/US8003635B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN101092432A (en) | 2007-12-26 |
ATE422944T1 (en) | 2009-03-15 |
DK1463563T3 (en) | 2009-04-20 |
WO2003051458A1 (en) | 2003-06-26 |
HK1069785A1 (en) | 2005-06-03 |
SI1463563T1 (en) | 2009-06-30 |
US7759333B2 (en) | 2010-07-20 |
ES2319399T3 (en) | 2009-05-07 |
EP1463563B1 (en) | 2009-02-18 |
KR20040063943A (en) | 2004-07-14 |
DE60231246D1 (en) | 2009-04-02 |
US20050032768A1 (en) | 2005-02-10 |
EP1463563A1 (en) | 2004-10-06 |
CN1620325A (en) | 2005-05-25 |
BR0214957A (en) | 2004-12-14 |
PL369607A1 (en) | 2005-05-02 |
AU2002351267B2 (en) | 2007-04-05 |
PT1463563E (en) | 2009-03-19 |
CA2470721C (en) | 2011-07-12 |
US20100204194A1 (en) | 2010-08-12 |
KR100951606B1 (en) | 2010-04-09 |
CY1108983T1 (en) | 2014-07-02 |
US8003635B2 (en) | 2011-08-23 |
JP2005513063A (en) | 2005-05-12 |
PL210225B1 (en) | 2011-12-30 |
CA2470721A1 (en) | 2003-06-26 |
AU2002351267A1 (en) | 2003-06-30 |
MXPA04005601A (en) | 2004-12-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8003635B2 (en) | Superoxide dismutase mimics for the treatment of ocular disorders and diseases | |
US20040116403A1 (en) | Superoxide dismutase mimics for the treatment of ocular disorders and diseases | |
US8067405B2 (en) | Superoxide dismutase mimics for the treatment of ocular disorders and diseases | |
US20110105453A1 (en) | Superoxide Dismutase Mimics For The Treatment Of Optic Nerve And Retinal Damage | |
AU2002351267B8 (en) | Superoxide dismutase mimics for the treatment of ocular disorders and diseases |